The origins and genetic interactions of KRAS mutations are allele- and tissue-specific.
The origins and genetic interactions of KRAS mutations are allele- and tissue-specific.
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DOI：
10.1038/s41467-021-22125-z
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发表时间：
2021-03-22
影响因子：
16.6
通讯作者：
Haigis KM
中科院分区：
文献类型：
--
作者：
Cook JH;Melloni GEM;Gulhan DC;Park PJ;Haigis KM
KRAS的突变激活促进癌症的发生和进展，特别是在结肠直肠、胰腺、肺和血浆中，特异性激活错义突变的发生率不同。尽管流行病学研究将特定等位基因与临床结果联系起来，但突变KRAS等位基因的独特临床特征的机制尚不清楚。在这里，我们分析了来自这四种肿瘤类型的13，492个样本，以检查与致癌KRAS突变相关的等位基因和组织特异性遗传特性。已知致突变机制的流行部分解释了观察到的KRAS激活突变谱。然而，许多等位基因的观测频率和预测频率之间存在很大差异，表明生物选择是突变等位基因组织特异性频率的基础。与已经确定与KRAS的每种突变形式相关的不同信号传导特性的实验研究一致，我们的遗传分析揭示每个KRAS等位基因与不同的组织特异性突变网络相关。此外，我们确定了与特定突变KRAS等位基因相关的组织特异性遗传依赖性。总的来说，这项分析表明，致癌KRAS突变的遗传相互作用是等位基因和组织特异性的，强调了驱动其临床后果的复杂性。KRAS基因通常在癌症中的几个热点密码子处突变，导致对KRAS蛋白的类似但不同的功能影响。在这里，作者研究了多种癌症类型中不同KRAS突变的遗传相互作用，并发现KRAS突变具有等位基因和组织特异性诱变起源，突变模式和依赖性相互作用。
Mutational activation of KRAS promotes the initiation and progression of cancers, especially in the colorectum, pancreas, lung, and blood plasma, with varying prevalence of specific activating missense mutations. Although epidemiological studies connect specific alleles to clinical outcomes, the mechanisms underlying the distinct clinical characteristics of mutant KRAS alleles are unclear. Here, we analyze 13,492 samples from these four tumor types to examine allele- and tissue-specific genetic properties associated with oncogenic KRAS mutations. The prevalence of known mutagenic mechanisms partially explains the observed spectrum of KRAS activating mutations. However, there are substantial differences between the observed and predicted frequencies for many alleles, suggesting that biological selection underlies the tissue-specific frequencies of mutant alleles. Consistent with experimental studies that have identified distinct signaling properties associated with each mutant form of KRAS, our genetic analysis reveals that each KRAS allele is associated with a distinct tissue-specific comutation network. Moreover, we identify tissue-specific genetic dependencies associated with specific mutant KRAS alleles. Overall, this analysis demonstrates that the genetic interactions of oncogenic KRAS mutations are allele- and tissue-specific, underscoring the complexity that drives their clinical consequences. The KRAS gene is often mutated at several hotspot codons in cancer, resulting in similar, yet distinct, functional impacts on the KRAS protein. Here, the authors examine the genetic interactions of the different KRAS mutations across multiple cancer types and discover that KRAS mutations have allele- and tissue-specific mutagenic origins, comutation patterns, and dependency interactions.
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遗传对人体组织基因表达的影响。
影响因子：
64.8
作者：
GTEx Consortium;Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group;Statistical Methods groups—Analysis Working Group;Enhancing GTEx (eGTEx) groups;NIH Common Fund;NIH/NCI;NIH/NHGRI;NIH/NIMH;NIH/NIDA;Biospecimen Collection Source Site—NDRI;Biospecimen Collection Source Site—RPCI;Biospecimen Core Resource—VARI;Brain Bank Repository—University of Miami Brain Endowment Bank;Leidos Biomedical—Project Management;ELSI Study;Genome Browser Data Integration &Visualization—EBI;Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz;Lead analysts:;Laboratory, Data Analysis &Coordinating Center (LDACC):;NIH program management:;Biospecimen collection:;Pathology:;eQTL manuscript working group:;Battle A;Brown CD;Engelhardt BE;Montgomery SB
通讯作者：
Montgomery SB
影响因子：
3.6
作者：
Bournet B;Muscari F;Buscail C;Assenat E;Barthet M;Hammel P;Selves J;Guimbaud R;Cordelier P;Buscail L
通讯作者：
Buscail L
影响因子：
9.3
作者：
Brubaker, Douglas K.;Paulo, Joao A.;Haigis, Kevin M.
通讯作者：
Haigis, Kevin M.
影响因子：
7
作者：
Angrand, Pierre-Olivier;Segura, Inmaculada;Acker-Palmer, Amparo
通讯作者：
Acker-Palmer, Amparo
影响因子：
64.5
作者：
Cancer Genome Atlas Network
通讯作者：
Cancer Genome Atlas Network